The Sweet Science of Glucose Transport
Authors: Vikas S. Sridhar, Joanne M. Bargman
Journal: Journal of the American Society of Nephrology (2022)

The maintenance of an osmotic gradient across the peritoneal membrane is essential to ultrafiltration (UF) in peritoneal dialysis (PD). Considering that glucose-based solutions remain the most frequently used solutions to generate this gradient, glucose transport across the peritoneal membrane is an important and clinically relevant process in PD. UF failure can be a limitation to long-term PD. Glucose exposure and associated alterations in the peritoneal membrane and peritoneal glucose transport are hypothesized to be key drivers of UF failure.1 An understanding of glucose transport in the peritoneum contributes to our understanding of UF-related complications in long-term PD, offering the potential to develop novel therapies. In this issue of JASN, Bergling et al.2 assess the contribution of glucose transporters (GLUTs) to peritoneal solute and water transport using known inhibitors of glucose transport. The three-pore model of peritoneal transport posits that intercellular "small pores" have radii of 40–55 Å and represent the majority of pores in the peritoneal microcirculation.3 The radius is significantly larger than the size of glucose molecules, resulting in unhindered diffusion down the concentration gradient from dialysate to blood. This movement of glucose out of the peritoneal cavity quickly diminishes the crystalloid osmotic gradient, limiting UF with glucose-based solutions to the first few hours of dwell time. Acquired UF failure over time has been hypothesized to be attributed to deleterious reduction in intercellular "small pore" fluid transport as well as interstitial changes that reduce hydraulic conductance of water.1 A connection between glucose transport and glucose-induced damage to peritoneal interstitial tissue has been proposed by Krediet,4 mediated by high levels of intracellular glucose. Impaired metabolism of high intracellular glucose alters the ratio of reduced nicotinamide adenine dinucleotide (NADH) to oxidized nicotinamide adenine dinucleotide (NAD+), mimicking a state of intracellular hypoxia. This "pseudohypoxic" state is hypothesized to promote tissue-level fibrosis and angiogenesis. Altered intracellular glucose metabolism first requires the transport of glucose from dialysate into peritoneal interstitial cells, introducing a role for peritoneal glucose transport in the pathophysiology of UF failure. GLUTs are divided into facilitative GLUTs, which enable glucose transport down a concentration gradient, and sodium glucose cotransporters (SGLTs) that couple glucose transport into the cell with sodium. Seven isoforms of GLUT and six of SGLT are currently known to exist. There have been a limited number of studies exploring GLUT expression in the peritoneum. Studies in human peritoneal mesothelial cells have demonstrated expression of GLUT1, GLUT3, SGLT1, and even SGLT2, although results have been inconsistent among studies.45–6 Exposure to high-glucose solutions in cell culture and animal models has also been demonstrated to upregulate GLUT expression, but again, results have varied across studies.4 The exact location of these transporters within the peritoneum and their role in PD remain unclear. Krediet4 hypothesized that increased uptake of glucose into the peritoneal interstitium, possibly facilitated by GLUT1, reduces the peritoneal glucose osmotic gradient and UF. Increased intracellular glucose and the associated pseudohypoxia are also hypothesized to upregulate hypoxia inducible factor-1, which increases GLUT1 expression, leading to a cycle that promotes UF failure over time.4 Novel applications of drugs affecting glucose transport in the field of PD offer additional insights into interactions between glucose transport and UF. Bergling et al.2 present results of a third study in a series of experiments exploring the effects of multiple glucose transport inhibitors in a rat model of PD. In the first of the three studies, the investigators demonstrated that the SGLT2 inhibitor empagliflozin had no effects on peritoneal glucose uptake.7 This contrasts with other studies where SGLT2 inhibition was associated with reduced peritoneal fibrosis and microvessel density, reduced peritoneal glucose absorption, and improved peritoneal UF.8,9 Considering the conflicting results and the absence of human data, it remains to be seen whether SGLT2 inhibitors have the potential to lower peritoneal glucose exposure and risk of acquired UF failure. Physiologically, however, peritoneal cells do not appear to absorb sodium, a finding that would be expected to accompany SGLT2-mediated glucose transport. For patients on PD, there is a strong rationale for using SGLT2 inhibitors to preserve residual kidney function and urine volume, although there is minimal experience or clinical trial evidence for their use in this population. SGLT2 inhibitors exert their effects in the proximal tubule, allowing synergism with other diuretics, such as loop diuretics. Furthermore, the cardiac benefits of SGLT2 inhibitors seem to be independent of kidney function and diabetes status, leading to benefits across a wide range of GFRs.10 The rationale for this study by Bergling et al.2 emerges from the second study of the series where phlorizin, a nonselective SGLT inhibitor, reduced peritoneal glucose absorption in the same rat model.11 The third study was conducted to distinguish if these effects were meditated by SGLT1 inhibition (considering the lack of effect with empagliflozin) or GLUT inhibition by the phlorizin metabolite, phloretin. Bergling et al.,2 therefore, repeated the experiments with phloretin and mizagliflozin, an SGLT1 inhibitor. Although mizagliflozin did not appear to have any effect on glucose transport, nonspecific GLUT inhibition with phloretin reduced peritoneal glucose absorption and improved median UF by >50%, presumably by prolonging the glucose osmotic gradient. These results are interesting, particularly considering novel GLUT inhibitors under development. With the existence of established and novel agents that inhibit glucose transport and the presence of conflicting results in preclinical studies, the time is ripe for human mechanistic and clinical trials to study the physiologic and clinical effects of glucose transport inhibitors in patients on PD. Considering the systemic effects of these agents and the ubiquitous nature of GLUTs, a key focus of these studies will be the safety and tolerability of glucose transport inhibitors in patients on PD. Disclosures J.M. Bargman has been a speaker and consultant for Baxter Healthcare and DaVita Healthcare Partners and a consultant for GSK. J.M. Bargman also reports consultancy agreements with Akebia, Bayer, Novartis, and Otsuka; honoraria from Akebia, Amgen, Baxter Healthcare, DaVita Healthcare Partners, and Glaxo Smith Kline; an advisory or leadership role on the editorial boards of CJASN, JASN, and Peritoneal Dialysis International; and speakers bureaus for Glaxo Smith Kline. V.S. Sridhar is supported by a Banting and Best Diabetes Centre postdoctoral fellowship at the University of Toronto, a Canadian Institutes of Health Research Canada Graduate Scholarship Doctoral Award, and the Department of Medicine Eliot Phillipson Clinician Scientist Training Program. V.S. Sridhar has received travel and conference support from Merck Canada. Funding None.